B Cell neoplasms account for a significant proportion of human lymphoid malignancies occurring in both immunodeficient hosts. Recently, it has been recognized that immunodeficient patients, including AIDS patients, develop a spectrum of EBV positive (EBV+) and negative (EBV-) B cell lymphomas with high frequency. Thus, a mechanism can be proposed whereby trans-activation of a B cell growth factor gene(s) leads to uncontrolled proliferation and may be sufficient to establish a transformed phenotype in the absence of EBV gene products and oncogene activating chromosomal translocations (c.g.c-myc, bc1-2). Our recent results indicate that 12-Kd human B cell growth factor (BCGF-12kD) is selectively expressed in transformed B cells but not in resting normal B cells. Furthermore, the growth of EBV- (but not EBV+) B cells is markedly inhibited by a treatment with TGF-beta. Thus these differences could underlie the pathogenic mechanisms for human B cell transformation. This project is directed at understanding the factors (cellular and viral) which regulate autocrine growth of EBV+ and EBV- B cell malignancies. Emphasis will be placed on BCGF-12kD, EBV regulatory proteins, and TGF- beta. Specifically, we will: 1) Expand our characterization of BCGF-12kD expression to a larger panel of EBV- and EBV+ B cell leukemias and lymphomas using an RNA based PCR assay: 2) assess the functional consequences of autocrine stimulation in EBV- and EBV+ cell lines by supplementing them with r-BCGF-12kD, by blocking autocrine pathways with an anti-BCGF-12kD monoclonal antibody, and by inhibiting BCGF-12kD expression with antisense oligonucleotides; 3) investigate the functional role of EBV trans-regulatory proteins (EBNA-2, LMP-1, and EBNA-3) in modulating BCGF- 12kD expression in EBV- B cell lines transfected with individual EBV genes; 40 examine the control mechanisms which modulate BCGF-12kD transcription n normal and malignant B cells using gel shift assays to characterize specific transcription factor binding and by transfecting a BCGF-CAT reporter gene construct into relevant B cell lines; and 5) better define the relationship of TGF-beta, BCGF-12kD, and EBV gene products in modulating autocrine B cell growth by investigating the effects of these species on the expression of, and signal transduction by, TGF-beta receptors. It is anticipated that these studies will lead to significant insights concerning the role of autocrine growth factors in the genesis and progression of B cell neoplasms in both immunocompetent and immunodeficient hosts and could also lead to novel therapeutic strategies.